• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Trends Mol Med. Author manuscript; available in PMC Jan 13, 2009.
Published in final edited form as:
PMCID: PMC2621332
NIHMSID: NIHMS84967

Pleiotropic effects of statin therapy

molecular mechanisms and clinical results

Abstract

Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or ‘pleiotropic’ effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance.

Pleiotropy of statins: beyond cholesterol lowering

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are principal therapeutic agents for the treatment of hypercholesterolemia. Several landmark clinical trials, such as Scandinavian Simvastatin Survival Study (4S) [1], Cholesterol and Recurrent Events (CARE) [2], Long-term Intervention with Pravastatin in Ischemia Disease (LIPID) [3], West of Scotland Coronary Prevention Study (WOSCOPS) [4], Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) [5] and the Heart Protection Study (HPS) [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1].

Figure 1
Isoprenoids and statins. Diagram of the cholesterol biosynthesis pathway and the effects of HMG-CoA-reductase inhibition by statins. Inhibition of small GTPase isoprenylation by statins leads to modulation of various cellular functions. Abbreviations: ...

Statins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might control diverse cellular functions, it is not surprising that statins might have additional effects beyond lipid lowering. Indeed, recent studies suggest that statins might be involved in immunomodulation [10], neuroprotection [11] and cellular senescence [12].

Cholesterol-lowering and statins

The Framingham Heart Study has demonstrated that elevated cholesterol is an important risk factor for cardiovascular diseases and lower cholesterol levels are associated with lower cardiovascular risks [13]. Recent evidence also shows that more intensive lowering of LDL-cholesterol by statins is associated with greater clinical benefits [14]. The mechanisms attributed to lipid lowering with statin therapy include atheromatous plaque stabilization, modification of the atherosclerosis progression and improved endothelial functions [15]. Hence, statins reduce cardiovascular events in not only hypercholesterolemic but also normocholesterolemic patients with coronary heart disease (CHD) or cardiovascular risks (Table 1).

Table 1
Characteristics and cardiovascular protection effects of statin clinical trials

Clinical trials with statins

Statins are the principal therapy for more than 25 million people at risk of cardiovascular disease worldwide. The 4S study was the first randomized controlled trial to show significant risk reduction in cardiovascular mortality in patients with coronary-artery disease. The evidence supporting the role for cholesterol in atherosclerosis is irrefutable because cholesterol contributes to the atherosclerotic lesion development [16]. For example, modified or oxidized LDL (oxLDL) can promote inflammatory processes in the arterial wall, activate monocytes or macrophages, increase free radical generation and lead to endothelial dysfunction [17]. Therefore, lowering of oxLDL levels by statins might contribute to some of the cholesterol-dependent effects of statins. Furthermore, data from meta-analysis of lipid-lowering trials suggest that lipid modification alone accounts for the clinical benefits associated with statin therapy [18]. However, both the level of efficacy and early treatment benefits as a result of statin therapy have so far been greater than the beneficial effects of non-statin lipid-lowering therapies. For example, in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy - Thrombolysis in Myocardial Infarction 22) study, the benefits of statin therapy in patients with acute coronary syndrome were observed within 30 days of treatment [14]. Furthermore, statins appear to have therapeutic benefits in diseases that are unrelated to elevated serum cholesterol levels, such as rheumatologic diseases [19] and ischemic stroke [1]. These findings suggest that statins might exert beneficial effects beyond cholesterol reduction.

Because of the effects of lipid lowering on atherosclerosis, it is not surprising that statins reduce morbidity and mortality in patients with ischemic heart failure [20] because the major etiology of ischemic heart failure is due to atherosclerosis, whereas non-ischemic heart failure is usually unrelated to atherosclerosis. What is surprising is that statins also improve heart function and survival in patients with non-ischemic heart failure [21-24]. Patients with severe heart failure without evidence of ischemic etiology have reduced all-cause mortality and are free from urgent transplantation on statin therapy [25]. Indeed, short-term statin therapy improves cardiac function, neurohormonal imbalance and symptoms associated with idiopathic dilated cardiomyopathy [21]. Thus, the improvements in heart function by statins might be owing to cholesterol-independent mechanisms. Currently, there are two large ongoing prospective trials, CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) and GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico - Insufficienza Cardiaca), which will help to determine whether statin therapy is effective in patients with ischemic and non-ischemic heart failure [26,27].

When comparing statin and non-statin lipid-lowering trials, statin-treatment trials demonstrate benefits within 5 years compared with greater than 7 years for non-statin trials [28,29]. Furthermore, subgroup analysis of WOSCOPS and CARE studies indicate that, despite comparable serum cholesterol levels among patients in the statin and placebo groups, patients who are treated with statin have 47% lower risk of developing subsequent events [2,4]. Recently, two clinical trials with ezetimibe support the notion of statin pleiotropy in humans. Ezetimibe is a lipid-lowering agent, which acts by decreasing cholesterol absorption in the intestine [30]. It is used alone or in combination with statin therapy to enhance lipid lowering [31]. In patients with heart failure, 4 weeks of simvastatin but not ezetimibe treatment improved endothelial function and reduced oxidative stress, despite comparable reduction in serum cholesterol levels [32]. Furthermore, compared with patients receiving combination therapy of ezetimibe and statin, patients receiving a higher dose of statin to achieve equal levels of cholesterol lowering have greater improvement in endothelial function [33] and lower platelet activation and chemokine levels [34]. Thus, the LDL-lowering benefits of ezetimibe remain to be determined.

Finally, evidence is emerging that patients with autoimmune diseases might also benefit from statin therapy. Clinical trials have demonstrated that statins can reduce morbidity in patients with multiple sclerosis [35,36]. Furthermore, in a 6 month, randomized, double-blind placebo-controlled clinical trial, patients with rheumatoid arthritis who received atorvastatin showed a reduction in disease activity [19]. However, it is too early to predict whether these promising data can translate into clinical benefit by statins in patients with autoimmune disease.

High-dose statin therapy

Recent clinical trials, such as MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering), TNT (Treating to New Targets), PROVE IT-TIMI 22 and SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), have shown that high-dose statins, especially atorvastatin 80-mg, can further reduce vascular risks compared with low- or moderate-dose statin therapy [14,20]. Consequently, in 2004, the National Cholesterol Education Program Adult Treatment Panel (NCEP) recommended an optional LDL goal of less than 70 mg/dl for those with highest risk, including patients with cardiovascular diseases with additional high-risk factors: diabetes mellitus, multiple cardiovascular risk factors, multiple risk factors of the metabolic syndrome or severe or poorly controlled risk factors, especially smoking [37]. It should be noted that the pleiotropic effects of statins are often greater with higher doses of statin. However, despite high statin dose, serious hepatic or musculoskeletal adverse effects are relatively low (0.6% and 1.3%, respectively) [14,20], although atorvastatin 80-mg is associated with higher rates of elevated hepatic transaminase and simvastatin 80-mg is associated with higher rates of myopathy and rhabdomyolysis. Therefore, although high-dose statin therapy appears to provide greater benefits, it is difficult to tease out whether the benefits are really due to lower cholesterol levels or to statin pleiotropy.

Statin and isoprenoids

Protein isoprenylation occurs on proteins containing a C-terminal CaaX motif, where C is cysteine, a is an aliphatic amino acid and X is any amino acid. In the human genome, there are more than 100 known and hypothetical prenylated CaaX-containing proteins. Protein isoprenylation permits the covalent attachment, subcellular localization and intracellular trafficking of membrane-associated proteins [8]. The lipophilic isoprenyl group enables these proteins to anchor to cell membranes, which, in most situations, is an essential requirement for biological function. Members of the Ras and Rho GTPase family are the major substrates for post-translational modification by prenylation [38]. These small GTP-binding proteins that cycle between the inactive GDP-bound state and active GTP-bound state are important regulators of actin cytoskeleton and intracellular signaling pathways (Box 1 and Figure 2).

Box 1. Small GTPase family of proteins

The family of small GTPases is monomeric guanine nucleotide-binding proteins of approximately 20-25 kDa. There are now approximately eight subfamilies that have been identified in mammals. The small GTPases cycle between GDP-bound (inactive) and GTP-bound (active) states. Through these interchanging states, they serve as molecular signaling switches that regulate growth, morphogenesis, cell migration, cytokinesis and molecular trafficking. Currently, the Ras and Rho GTPase families are of special interest because they transduce extracellular stimuli to multiple intracellular signaling pathways [43].

Ras

Mutations in the Ras family of proto-oncogenes are found in 20-30% of human tumors. Inappropriate activation of the Ras has a key role in signal transduction, proliferation and malignant transformation.

Rho

Rho, Rac and Cdc42 are the best characterized subfamilies and regulate actin cytoskeletal change, microtubule dynamics, vesicle trafficking, cell polarity and cell-cycle progression.

Other small GTPases

Other small GTPases include Rab, Rap, Ran, Rheb, Rad, Rit and Arf. They are important for many cellular processes, such as membrane trafficking, nucleocytoplasmic transport and the regulation of cell proliferation.

Figure 2
Regulation of the Rho GTPase cycle. Rho proteins cycle between a cytosolic, inactive GDP-bound state and an active, membrane, GTP-bound state. This cycle is controlled by guanine nucleotide-exchange factors (GEF), GTPase-activating proteins (GAP) and ...

Each member of the Rho GTPase family, which consists of RhoA, Rac and Cdc42, serves specific functions in terms of cell shape, motility, secretion and proliferation. For example, the activation of Cdc42 induces actin-rich surface protrusions, whereas activation of Rac1 leads to the formation of lamellipodia and membrane ruffles. By contrast, the activation of Rho and its downstream target, Rho-associated protein kinase (ROCK), regulates calcium-insensitive vascular smooth-muscle contraction in hypertension [39] and coronary spasm [40]. Because three-dimensional colocalization of intracellular proteins is regulated by cytoskeletal rearrangements, changes in statin-induced actin cytoskeleton could affect intracellular transport, membrane trafficking, mRNA stability and gene transcription. Indeed, statins have been reported to cause alterations in the actin cytoskeleton and the assembly of focal adhesion complexes by inhibiting RhoA and Rac1 isoprenylation [41].

Thus, statins might affect vascular function through the modulation of signaling proteins that depend on post-translational modification with isoprenoid.

Statins and Rho

The biological effects of Rho are mediated by its downstream effectors, including ROCK, protein kinase N-related kinases, citron kinase, rhotekin, mDia and the myosin-binding subunit of myosin light-chain (MLC) phosphatase [42]. Although the precise roles of these many effectors remain to be determined, the best characterized is the effect of ROCK on the actin cytoskeleton. ROCK phosphorylates and inhibits the myosin-binding subunit of MLC phosphatase. Inhibition of MLC phosphatase increases MLC phosphorylation and myosin contractility, which drive the formation of stress fibers and focal adhesions [43]. ROCK activity is often elevated in disorders of the cardiovascular system [14]. Thus, statins could affect vascular smooth-muscle contraction at least partially through effects on Rho/ROCK [39,43]. Through inhibition of isoprenylation of Rho, translocation of Rho to the cell membrane is inhibited and the downstream activation of ROCK is reduced [44]. Indeed, ROCK inhibitors prevent cerebral vasospasm after subarachnoid hemorrhage [45], inhibit the development of atherosclerosis [46] and prevent arterial remodeling after vascular injury [47].

The Rho/ROCK pathway could also regulate cellular functions other than the actin cytoskeleton. For example, ROCK can phosphorylate insulin receptor substrate-1 (IRS-1) and modulate the insulin/PI3K/Akt pathway [48]. The Rho/ROCK pathway is involved in oxidative stress, aortic stiffness and changes in blood pressure [49]. Furthermore, ROCK regulates cell survival through phosphorylation of the protein kinase B/Akt and FOXO (see Glossary) [50]. ROCK can also regulate adipogenesis and myogenesis. In p190-B Rho GAP-deficient mice, the Rho/ROCK pathway is activated chronically and there is a defect in adipogenesis with a predilection towards myogenesis [51]. Other processes or conditions involving the RhoA/ROCK pathway include angiogenesis [52], hypertension [39], cardiac hypertrophy [53], perivasclar fibrosis [54] and pulmonary hypertension [52]. Fasudil, a selective ROCK inhibitor, improves endothelial function in patients with coronary artery disease [55]. These findings suggest that ROCK inhibition might contribute to some of the pleiotropic effects of statin therapy.

Statins and Rac

Two important effector-response pathways lie downstream of Rac: cytoskeletal remodeling and reactive oxygen species (ROS) generation. Rac1 influences multiple cytoskeletal remodeling proteins, such as Wiskott-Aldrich syndrome protein, calmodulin-binding GTPase-activating proteins and p21-activated kinase. Rac1 also binds to p67phox and leads to activation of the NADPH oxidase system and subsequent generation of ROS. Indeed, Rac activity is closely related to ROS production and ROS generated by NADPH oxidase in response to growth factors and inflammatory cytokines is mediated by Rac [56]. Importantly, statins inhibit Rac1-mediated NADPH oxidase activity and thereby reduce angiotensin II-induced ROS production and hypertrophy in smooth muscle and heart [57,58]. The activation of Rac1 in the vascular wall has been associated with atherosclerosis, neointimal proliferation, cardiac hypertrophy and endothelial dysfunction [59]. Rac1 has multiple roles in diverse cellular processes and cardiovascular physiology [60]. Thus, Rac1 inhibition might also contribute to some of the pleiotropic effects of statins.

Statins and vascular dysfunction

The endothelium produces vasoactive substances in response to environmental factors and serves as an important autocrine and paracrine organ that regulates the vascular-wall contractile state and cellular composition. Endothelium-derived nitric oxide (NO) mediates vasodilation, inhibits platelet aggregation and leukocyte adhesion and decreases vascular smooth-muscle proliferation [61]. Endothelium-derived NO, therefore, is protective for the vasculature and decreased NO bioavailability is often associated with increased risk of cardiovascular disease [62]. As mentioned, endothelial dysfunction is one of the earliest manifestations of atherosclerosis [63].

Elevated serum cholesterol levels lead to endothelial dysfunction [64]. The mechanism by which LDL-cholesterol causes endothelial dysfunction and decreases NO bioactivity involves downregulation of endothelial NOS expression, decreased receptor-mediated NO release [65] and decreased NO bioavailability owing to increase in ROS production [66]. Furthermore, oxLDL can also recruit leukocytes to the arterial wall and activates NF-κB, a major proinflammatory transcription factor that is crucial for the induction of vascular cell adhesion molecule (VCAM)-1 and monocyte chemotactic protein (MCP)-1 [67].

Statins improve endothelial function by cholesterol-dependent and -independent mechanisms. Clinical trials have shown that LDL apheresis, which removes plasma LDL particles physically, can improve endothelium-dependent vasomotion through acute reduction in serum cholesterol levels [68]. Cholesterol lowering modifies atherosclerotic-plaque biology, thereby decreasing vascular inflammation and leukocyte activation [69]. Thus, statins can improve endothelial function through reduction in serum cholesterol levels. However, in some studies, statins improve endothelial function before significant reduction in serum cholesterol levels occurs [70,71]. This, in part, is mediated by the upregulation of endothelial nitric oxide synthase (eNOS) in the presence of hypoxia [72] and oxLDL [73].

Statins affect eNOS expression and activity mainly through three mechanisms [74]. First, statins increase eNOS expression by prolonging eNOS mRNA half-life rather than by inducing eNOS gene transcription. The mechanism is owing to inhibition of RhoA geranylgeranylation, alteration of the cytoskeleton and localization of the eNOS mRNA [75]. Second, statins reduce caveolin-1 abundance. Caveolin-1 is an integral membrane protein and binds to eNOS in caveolae, thereby inhibiting NO production directly [76]. Third, statins can activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt pathway [77]. Akt is a serine/threonine kinase that regulates various cellular functions, such as survival, growth and proliferation. Because Akt, in turn, phosphorylates and activates eNOS, statins can also increase eNOS activity through the PI3K/Akt pathway [78].

Several vasoconstricting agents, such as endothelin-1 (ET-1) or angiotensin II, counteract the vasodilating effect of NO and might contribute to the development of atherosclerosis. ET-1 acts as a potent mitogenic agent, which promotes neointima formation and proliferation of smooth muscle cells [79]. ET-1 is found to be elevated in patients with severe atherosclerosis [80]. Statins inhibit the expression of preproET-1 [81] and downregulate endothelin and angiogensin subtype 1 receptors [82,83] in a RhoA-dependent manner.

Statins also affect the fibrinolytic system of vascular smooth muscle and endothelial cells [84]. Plasminogen activator inhibitor type-1 (PAI-1) is the major endogenous inhibitor of tissue plasminogen activator. Elevated PAI-1 level is an independent cardiovascular risk factor and is associated with atherothrombotic disease [85,86]. Statins increase the expression of tissue-type plasminogen activator and inhibit the expression of PAI-1 [73]. The inhibitory effect of statins on PAI-1 expression is mediated, in part, through the PI3K/Akt pathway [87].

Statins also induce the expression of heme oxygenase-1 (HO-1) [88]. HO-1 is a stress-response protein, which is induced in response to UV radiation, cytokines and free radicals. Induction of HO-1 leads to the degradation of heme to carbon monoxide and biliverdin. Biliverdin is then converted to the antioxidant bilirubin [89]. Interestingly, HO-1 prevents the development of atherosclerosis in mice [90]. Further studies are needed to determine whether some of the anti-atherosclerotic effects of statins are mediated by HO-1 induction.

Statins and immunomodulation

Inflammatory cells have an important role in the pathogenesis of atherosclerosis [91]. Immunomodulation by statins, therefore, might contribute to some of the cholesterol-independent effects of statins. For example, simvastatin inhibits MHC II expression, which is upregulated in myocarditis, multiple sclerosis and rheumatoid arthritis. Antigen presentation requires endocytosis of antigen, internal processing and presentation of MHC IImolecules at the cell surface. These processes all involve changes in the actin cytoskeleton, which are controlled by small GTPases. Indeed, the inhibitory effect of statins on MHC II expression is reversed by mevalonate and GGPP but not squalene (Figure 1), suggesting the involvement of small GTPases as the underlying mechanism [92]. Similarly, Cdc42 and Rac regulate the ability of dendritic cells to present antigen to T cells [93].

Statins decrease macrophage expression of tumor necrosis factor and interleukin (IL)-1β and also inhibit the proliferation of peripheral blood mononuclear cells [94]. Statins also regulate T-cell phenotype. Statins prevent experimental T helper 1 (Th1)-mediated autoimmune diseases [95] and induce IL-4-dependent Th2-cell differentiation [96] and the secretion of anti-inflammatory Th2-type cytokines [97]. Finally, statins can also bind to a novel allosteric site within the β2-integrin function-associated antigen-1 protein, independent of mevalonate production [98]. Inhibition of β2-integrin function-associated antigen-1 can decrease lymphocyte adhesion to ICAM-1 and impair T-cell co-stimulation [98]. This is one of the few reported pleiotropic effects of statins that does not involve the inhibition of small GTPases.

Concluding remarks

Statins exert many effects beyond cholesterol lowering. These effects include improving endothelial function, decreasing vascular inflammation, inhibiting smooth-muscle proliferation and immunomodulation. Recent studies suggest that most of these effects are mediated through inhibition of isoprenoid synthesis, with subsequent effects on multiple downstream signaling pathways (Box 2). However, further studies are needed to determine to what extent these pleiotropic effects contribute to the clinical benefits of statin therapy.

Box 2. Outstanding issues

Combination therapies

It is important to address the clinical importance of statin therapy in combination with other lipid-lowering strategies in lowering cardiovascular risks.

Statin and cancer

Large, prospective and randomized trials are needed to determine the effect of statins in relation to cancer prevention and treatment.

Differential effects of statins

It is not known whether different statins have different efficacy in inhibiting isoprenylation and therefore different potency for pleiotropic effects.

Statins and aging

Recent studies suggest that statins might be useful as an anti-aging therapy [99]. However, further studies are required to address and elucidate the role of statins in this area.

Glossary

AKT/PKB and FOXO
This term refers to serine-threonine protein kinase Akt (protein kinase B) and its downstream target forkhead transcription factors. It is an important regulator of cellular growth, survival and senescence.
Caveolae
Caveolae refers to approximately 50-100 nm invaginations of the plasma membrane in terminal differentiated cells. Caveolin is the principle protein of caveolae. Caveolae have important roles in endocytosis, oncogenesis, uptake of pathogenic bacteria and signal transduction.
Isoprenylation
This term refers to post-translational modification of proteins with isoprenoids. Isoprenylation of proteins is important for protein trafficking and compartmentalization.
Neointima
This term refers to vascular remodeling within the internal elastic lamina formed by a thickened layer of vascular smooth muscle and inflammatory cells. Formation of neointima occurs in response to vascular injury.
Reactive oxygen species, NADPH oxidase and p67phox
Reactive oxygen species refers to oxygen-derived free radicals. They are formed mainly through three processes: (i) they are a byproduct of cellular respiration, (ii) they are synthesized by dedicated enzymes such as NADPH oxidase or myeloperoxidase and (iii) they can be formed by ionizing radiation injury. The cytosolic protein p67phox is a component of NADPH oxidase.

References

1. Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet. 1994;344:1383–1389. [PubMed]
2. Sacks FM, et al. Cholesterol and Recurrent Events Trial investigators The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N. Engl. J. Med. 1996;335:1001–1009. [PubMed]
3. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N. Engl. J. Med. 1998;339:1349–1357. [PubMed]
4. Shepherd J, et al. West of Scotland Coronary Prevention Study Group Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N. Engl. J. Med. 1995;333:1301–1307. [PubMed]
5. Downs JR, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. J. Am. Med. Assoc. 1998;279:1615–1622. [PubMed]
6. Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20.536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22. [PubMed]
7. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343:425–430. [PubMed]
8. Van Aelst L, D’Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev. 1997;11:2295–2322. [PubMed]
9. Maurer-Stroh S, et al. Towards complete sets of farnesylated and geranylgeranylated proteins. PLoS Comput. Biol. 2007;3:e66. [PMC free article] [PubMed]
10. Greenwood J, et al. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat. Rev. Immunol. 2006;6:358–370. [PMC free article] [PubMed]
11. Kivipelto M, et al. Statin therapy in Alzheimer’s disease. Lancet Neurol. 2005;4:521–522. [PubMed]
12. Brouilette SW, et al. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet. 2007;369:107–114. [PubMed]
13. Sytkowski PA, et al. Changes in risk factors and the decline in mortality from cardiovascular disease. The Framingham Heart Study. N. Engl. J. Med. 1990;322:1635–1641. [PubMed]
14. Cannon CP, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 2004;350:1495–1504. [PubMed]
15. Archbold RA, Timmis AD. Cholesterol lowering and coronary artery disease: mechanisms of risk reduction. Heart. 1998;80:543–547. [PMC free article] [PubMed]
16. Ross R. The pathogenesis of atherosclerosis - an update. N. Engl. J. Med. 1986;314:488–500. [PubMed]
17. Pinderski LJ, et al. Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient Mice by altering lymphocyte and macrophage phenotypes. Circ. Res. 2002;90:1064–1071. [PubMed]
18. Robinson JG, et al. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J. Am. Coll. Cardiol. 2005;46:1855–1862. [PubMed]
19. McCarey DW, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363:2015–2021. [PubMed]
20. LaRosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 2005;352:1425–1435. [PubMed]
21. Node K, et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation. 2003;108:839–843. [PMC free article] [PubMed]
22. Horwich TB, et al. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J. Am. Coll. Cardiol. 2004;43:642–648. [PubMed]
23. Foody JM, et al. Statins and mortality among elderly patients hospitalized with heart failure. Circulation. 2006;113:1086–1092. [PubMed]
24. Go AS, et al. Statin therapy and risks for death and hospitalization in chronic heart failure. J. Am. Med. Assoc. 2006;296:2105–2111. [PubMed]
25. Ray JG, et al. Statin use and survival outcomes in elderly patients with heart failure. Arch. Intern. Med. 2005;165:62–67. [PubMed]
26. Tavazzi L, et al. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur. J. Heart Fail. 2004;6:635–641. [PubMed]
27. Kjekshus J, et al. A statin in the treatment of heart failure? Controlled rosuvastatin multinational study in heart failure (CORONA): study design and baseline characteristics. Eur. J. Heart Fail. 2005;7:1059–1069. [PubMed]
28. The Lipid Research Clinics The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. J. Am. Med. Assoc. 1984;251:365–374. [PubMed]
29. Buchwald H, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH) N. Engl. J. Med. 1990;323:946–955. [PubMed]
30. Sudhop T, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002;106:1943–1948. [PubMed]
31. Bruckert E, et al. Perspectives in cholesterol-lowering therapy: the role of ezetimibe, a new selective inhibitor of intestinal cholesterol absorption. Circulation. 2003;107:3124–3128. [PubMed]
32. Landmesser U, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation. 2005;111:2356–2363. [PubMed]
33. Fichtlscherer S, et al. Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for ‘pleiotropic’ functions of statin therapy. Eur. Heart J. 2006;27:1182–1190. [PubMed]
34. Piorkowski M, et al. Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets? J. Am. Coll. Cardiol. 2007;49:1035–1042. [PubMed]
35. Sena A, et al. Therapeutic potential of lovastatin in multiple sclerosis. J. Neurol. 2003;250:754–755. [PubMed]
36. Vollmer T, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363:1607–1608. [PubMed]
37. Grundy SM, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239. [PubMed]
38. Hall A. Rho GTPases and the actin cytoskeleton. Science. 1998;279:509–514. [PubMed]
39. Uehata M, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389:990–994. [PubMed]
40. Katsumata N, et al. Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1β Circulation. 1997;96:4357–4363. [PubMed]
41. Laufs U, et al. Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription. Circulation. 2000;102:3104–3110. [PubMed]
42. Bishop AL, Hall A. Rho GTPases and their effector proteins. Biochem. J. 2000;348:241–255. [PMC free article] [PubMed]
43. Burridge K, Wennerberg K. Rho and Rac take center stage. Cell. 2004;116:167–179. [PubMed]
44. Liao JK, Laufs U. Pleiotropic effects of statins. Annu. Rev. Pharmacol. Toxicol. 2005;45:89–118. [PMC free article] [PubMed]
45. Shibuya M, et al. Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial. J. Neurosurg. 1992;76:571–577. [PubMed]
46. Mallat Z, et al. Rho-associated protein kinase contributes to early atherosclerotic lesion formation in mice. Circ. Res. 2003;93:884–888. [PubMed]
47. Sawada N, et al. Inhibition of rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries. Circulation. 2000;101:2030–2033. [PubMed]
48. Farah S, et al. A rho-associated protein kinase, ROKα, binds insulin receptor substrate-1 and modulates insulin signaling. J. Biol. Chem. 1998;273:4740–4746. [PubMed]
49. Noma K, et al. Roles of rho-associated kinase and oxidative stress in the pathogenesis of aortic stiffness. J. Am. Coll. Cardiol. 2007;49:698–705. [PMC free article] [PubMed]
50. Nishiyama T, et al. Inactivation of Rho/ROCK signaling is crucial for the nuclear accumulation of FKHR and myoblast fusion. J. Biol. Chem. 2004;279:47311–47319. [PubMed]
51. Sordella R, et al. Modulation of Rho GTPase signaling regulates a switch between adipogenesis and myogenesis. Cell. 2003;113:147–158. [PubMed]
52. Hyvelin JM, et al. Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation. Circ. Res. 2005;97:185–191. [PubMed]
53. Higashi M, et al. Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ. Res. 2003;93:767–775. [PubMed]
54. Rikitake Y, et al. Decreased perivascular fibrosis but not cardiac hypertrophy in ROCK1+/- haploinsufficient mice. Circulation. 2005;112:2959–2965. [PMC free article] [PubMed]
55. Nohria A, et al. Rho kinase inhibition improves endothelial function in human subjects with coronary artery disease. Circ. Res. 2006;99:1426–1432. [PMC free article] [PubMed]
56. Sundaresan M, et al. Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. Biochem. J. 1996;318:379–382. [PMC free article] [PubMed]
57. Takemoto M, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J. Clin. Invest. 2001;108:1429–1437. [PMC free article] [PubMed]
58. Wassmann S, et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol. Pharmacol. 2001;59:646–654. [PubMed]
59. Gregg D, et al. Rac regulates cardiovascular superoxide through diverse molecular interactions: more than a binary GTP switch. Am. J. Physiol. Cell Physiol. 2003;285:C723–C734. [PubMed]
60. Hordijk PL. Regulation of NADPH oxidases: the role of Rac proteins. Circ. Res. 2006;98:453–462. [PubMed]
61. Janssens S, et al. Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats. Circulation. 1998;97:1274–1281. [PubMed]
62. Liao JK, et al. Differential impairment of vasodilator responsiveness of peripheral resistance and conduit vessels in humans with atherosclerosis. Circ. Res. 1991;68:1027–1034. [PubMed]
63. Werns SW, et al. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation. 1989;79:287–291. [PubMed]
64. Steinberg D, et al. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl. J. Med. 1989;320:915–924. [PubMed]
65. Liao JK. Inhibition of Gi proteins by low density lipoprotein attenuates bradykinin-stimulated release of endothelial-derived nitric oxide. J. Biol. Chem. 1994;269:12987–12992. [PubMed]
66. Alderson LM, et al. LDL enhances monocyte adhesion to endothelial cells in vitro. Am. J. Pathol. 1986;123:334–342. [PMC free article] [PubMed]
67. Collins T, Cybulsky MI. NF-κB: pivotal mediator or innocent bystander in atherogenesis? J. Clin. Invest. 2001;107:255–264. [PMC free article] [PubMed]
68. Tamai O, et al. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. Circulation. 1997;95:76–82. [PubMed]
69. Lima JA, et al. Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation. 2004;110:2336–2341. [PubMed]
70. Anderson TJ, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N. Engl. J. Med. 1995;332:488–493. [PubMed]
71. O’Driscoll G, et al. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997;95:1126–1131. [PubMed]
72. Laufs U, et al. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J. Biol. Chem. 1997;272:31725–31729. [PubMed]
73. Essig M, et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins. Circ. Res. 1998;83:683–690. [PubMed]
74. Laufs U, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97:1129–1135. [PubMed]
75. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J. Biol. Chem. 1998;273:24266–24271. [PubMed]
76. Plenz GA, et al. Differential modulation of caveolin-1 expression in cells of the vasculature by statins. Circulation. 2004;109:e7–e8. [PubMed]
77. Kureishi Y, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat. Med. 2000;6:1004–1010. [PMC free article] [PubMed]
78. Simoncini T, et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature. 2000;407:538–541. [PMC free article] [PubMed]
79. Yang Z, et al. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade. Circulation. 1999;100:5–8. [PubMed]
80. Lerman A, et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N. Engl. J. Med. 1991;325:997–1001. [PubMed]
81. Hernandez-Perera O, et al. Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ. Res. 2000;87:616–622. [PubMed]
82. Ichiki T, et al. Downregulation of angiotensin II type 1 receptor by hydrophobic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 2001;21:1896–1901. [PubMed]
83. Xu CB, et al. Reduction of bFGF-induced smooth muscle cell proliferation and endothelin receptor mRNA expression by mevastatin and atorvastatin. Biochem. Pharmacol. 2002;64:497–505. [PubMed]
84. Bourcier T, Libby P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler. Thromb. Vasc. Biol. 2000;20:556–562. [PubMed]
85. Huber K, et al. Plasminogen activator inhibitor type-1 in cardiovascular disease. Status report 2001. Thromb. Res. 2001;103(Suppl 1):S7–S19. [PubMed]
86. Nordt TK, et al. Plasminogen activator inhibitor type-1 (PAI-1) and its role in cardiovascular disease. Thromb. Haemost. 1999;82(Suppl 1):14–18. [PubMed]
87. Mukai Y, et al. Phosphatidylinositol 3-kinase/protein kinase Akt negatively regulates plasminogen activator inhibitor type 1 expression in vascular endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 2007;292:H1937–H1942. [PMC free article] [PubMed]
88. Lee TS, et al. Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation. 2004;110:1296–1302. [PubMed]
89. Lee TS, Chau LY. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat. Med. 2002;8:240–246. [PubMed]
90. Juan SH, et al. Adenovirus-mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2001;104:1519–1525. [PubMed]
91. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–874. [PubMed]
92. Kwak B, et al. Statins as a newly recognized type of immunomodulator. Nat. Med. 2000;6:1399–1402. [PubMed]
93. Nobes C, Marsh M. Dendritic cells: new roles for Cdc42 and Rac in antigen uptake? Curr. Biol. 2000;10:R739–R741. [PubMed]
94. Pahan K, et al. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J. Clin. Invest. 1997;100:2671–2679. [PMC free article] [PubMed]
95. Greenwood J, et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 2003;17:905–907. [PMC free article] [PubMed]
96. Aprahamian T, et al. Simvastatin treatment ameliorates autoimmune disease associated with accelerated atherosclerosis in a murine lupus model. J. Immunol. 2006;177:3028–3034. [PMC free article] [PubMed]
97. Youssef S, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420:78–84. [PubMed]
98. Weitz-Schmidt G, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat. Med. 2001;7:687–692. [PubMed]
99. Assmus B, et al. HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ. Res. 2003;92:1049–1055. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...